Synapse - High transposable element expression in sarcomas is associated with increased immune infiltrates and improved outcomes including after immunotherapy

High transposable element expression in sarcomas is associated with increased immune infiltrates and improved outcomes including after immunotherapy Journal Article

Authors:	Nacev, B. A.; Bradic, M.; Woo, H. J.; Richards, A. L.; Kelly, C. M.; Dickson, M. A.; Gounder, M. M.; Keohan, M. L.; Chi, P.; Movva, S.; Maki, R. G.; Slotkin, E. K.; Rosenbaum, E.; Avutu, V.; Chan, J. E.; Banks, L. B.; Adamson, T.; Singer, S.; Antonescu, C. R.; Tap, W. D.; Donoghue, M. T. A.; D'Angelo, S. P.
Article Title:	High transposable element expression in sarcomas is associated with increased immune infiltrates and improved outcomes including after immunotherapy
Abstract:	<p>Background Response to immune checkpoint inhibition (ICI) in sarcomas is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. Thus, we investigated whether the expression of transposable elements (TEs), which are epigenetically silenced and can stimulate antitumor immunity, influence ICI outcomes and immune infiltrates in common sarcoma subtypes.Methods We used transcriptomic data to assign immune enhanced versus immune depleted status to 67 pretreatment and on-treatment biopsies of sarcomas from patients treated on ICI trials, along with additional cohorts from The Cancer Genome Atlas (TCGA) and an independent ICI trial (SARC028). A machine learning technique (lasso-penalized logistic regression) controlled for sarcoma subtype was used to determine if TE and epigenetic regulatory gene expression predict immune infiltrates. Correlations between top features in these models and sarcoma immune infiltrates, immune pathway expression, and clinical outcomes were explored.Results Expression of TEs and epigenetic regulators significantly predicted immune enhanced status. TE subfamilies and Ikaros family zinc finger 1 (IKZF1), a chromatin-modulating transcription factor, were significantly contributory. TE and IKZF1 expression positively correlated with tumor immune infiltrates, inflammatory pathways, and improved clinical outcomes, and increased in tumors that gained immune infiltrates during ICI treatment. TE and IKZF1 expression similarly correlated with overall survival and immune features in a TCGA cohort. In an additional cohort of patients with sarcoma treated with ICI, IKZF1 expression correlated with progression-free survival and inflammatory features.Conclusions TE and IKZF1 expression warrant further translational investigation as potential biomarkers of tumor immune infiltrates and outcomes following ICI treatment, and as therapeutic targets in sarcomas.</p>
Keywords:	survival; sarcoma; solid tumors; soft-tissue sarcoma; landscape; blockade; open-label; immune checkpoint inhibitor; nivolumab; package; cancer; pembrolizumab
Journal Title:	Journal for ImmunoTherapy of Cancer
Volume:	13
Issue:	9
ISSN:	2051-1426
Publisher:	Biomed Central Ltd
Date Published:	2025-09-01
Start Page:	e012357
Language:	English
ACCESSION:	WOS:001564891400001
DOI:	10.1136/jitc-2025-012357
PROVIDER:	wos
PMCID:	PMC12414182
PUBMED:	40912740
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Wos